Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I.
Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I.
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DOI：
10.1371/journal.pone.0042904
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Sedensky MM
中科院分区：
文献类型：
--
作者：
Quintana A;Morgan PG;Kruse SE;Palmiter RD;Sedensky MM
麻醉剂是常规使用，但其作用机制尚未完全了解。体外研究表明，GABAA和NMDA受体都受到麻醉剂的调节，但整个动物模型并不支持这些受体作为全身麻醉的唯一效应物的作用。发现在C.线虫和儿童的研究表明，线粒体复合物I的缺陷可引起对挥发性麻醉剂的超敏反应。在这里，我们测试了一个基因敲除（KO）小鼠，由于Ndufs 4基因（编码复合物I的一个亚基）的失活，复合物I的功能降低。我们用两种挥发性和两种非挥发性麻醉剂测试了这些KO小鼠。在出生后（PN）第23至27天，用异氟烷、氟烷、丙泊酚或氯胺酮麻醉KO和野生型（WT）小鼠，并测试对夹尾反应的丧失（异氟烷和氟烷）或翻正反射的丧失（丙泊酚和氯胺酮）。KO小鼠对异氟烷和氟烷的敏感性是WT小鼠的2.5 - 3倍。KO小鼠对丙泊酚的敏感性是2倍，但对氯胺酮有抵抗力。这些麻醉剂敏感性的变化是哺乳动物中记录的最大变化。
Anesthetics are in routine use, yet the mechanisms underlying their function are incompletely understood. Studies in vitro demonstrate that both GABAA and NMDA receptors are modulated by anesthetics, but whole animal models have not supported the role of these receptors as sole effectors of general anesthesia. Findings in C. elegans and in children reveal that defects in mitochondrial complex I can cause hypersensitivity to volatile anesthetics. Here, we tested a knockout (KO) mouse with reduced complex I function due to inactivation of the Ndufs4 gene, which encodes one of the subunits of complex I. We tested these KO mice with two volatile and two non-volatile anesthetics. KO and wild-type (WT) mice were anesthetized with isoflurane, halothane, propofol or ketamine at post-natal (PN) days 23 to 27, and tested for loss of response to tail clamp (isoflurane and halothane) or loss of righting reflex (propofol and ketamine). KO mice were 2.5 - to 3-fold more sensitive to isoflurane and halothane than WT mice. KO mice were 2-fold more sensitive to propofol but resistant to ketamine. These changes in anesthetic sensitivity are the largest recorded in a mammal.
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DOI：
10.1056/nejmra0808281
发表时间：
2010-12-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brown EN;Lydic R;Schiff ND
通讯作者：
Schiff ND
影响因子：
11.4
作者：
Heurteaux, C;Guy, N;Lazdunski, M
通讯作者：
Lazdunski, M
影响因子：
5.3
作者：
Hartman, PS;Ishii, N;Sedensky, MM
通讯作者：
Sedensky, MM
影响因子：
5.7
作者：
Petrenko, AB;Yamakura, T;Sakimura, K
通讯作者：
Sakimura, K
影响因子：
4.8
作者：
Kayser, EB;Morgan, PG;Sedensky, MM
通讯作者：
Sedensky, MM